MACROPHAGE MICROGLIAL-MEDIATED PRIMARY DEMYELINATION AND MOTOR DISEASE INDUCED BY THE CENTRAL-NERVOUS-SYSTEM PRODUCTION OF INTERLEUKIN-3 INTRANSGENIC MICE

Activated macrophage/microglia may mediate tissue injury in a variety of CNS disorders. To examine this, transgenic mice were developed in w hich the expression of a macrophage/microglia activation cytokine, int erleukin-3 (IL-3), was targeted to astrocytes using a murine glial fib rillary acidic protein fusion gene. Transgenic mice with low levels of IL-3 expression developed from 5 mo of age, a progressive motor disor der characterized at onset by impaired rota-rod performance. In sympto matic transgenic mice, multi-focal, plaquelike white matter lesions we re present in cerebellum and brain stem. Lesions showed extensive prim ary demyelination and remyelination in association with the accumulati on of large numbers of proliferating and activated foamy macrophage/mi croglial cells. Many of these cells also contained intracisternal crys talline pole-like inclusions similar to those seen in human patients w ith multiple sclerosis. Mast cells were also identified while lymphocy tes were rarely, if at all present. Thus, chronic CNS production of lo w levels of IL-3 promotes the recruitment, proliferation and activatio n of macrophage/microglial cells in white matter regions with conseque nt primary demyelination and motor disease. This transgenic model exhi bits many of the features of human inflammatory demyelinating diseases including multiple sclerosis and HIV leukoencephalopathy.